Novel proapoptotic effect of hepatocyte growth factor: Synergy with palmitate to cause pancreatic β-cell apoptosis

Increasing evidence suggests that elevation of plasma fatty acids that often accompanies insulin resistance contributes to β-cell insufficiency in obesity-related type 2 diabetes. Circulating levels of hepatocyte growth factor (HGF) are increased in humans with metabolic syndrome and obesity. HGF is known to protect β-cells against streptozotocin and during islet engraftment. However, whether HGF is a β-cell prosurvival factor in situations of excessive lipid supply has not been deciphered. Mice overexpressing HGF in the β-cell [rat insulin type II promoter (RIP)-HGF transgenic mice] fed with standard chow display improved glucose homeostasis and increased β-cell mass and proliferation compared with normal littermates. However, after 15wkof high-fat feeding, glucose homeostasis and β-cell expansion and proliferation are indistinguishable between normal and transgenic mice. Interestingly, RIP-HGF transgenic mouse β-cells and normal β-cells treated with HGF display increased sensitivity to palmitate-mediated apoptosis in vitro. Palmitate completely eliminates Akt and Bad phosphorylation in RIP-HGF transgenic mouse islets. HGF-overexpressing islets also show significantly decreased AMP-activated protein kinase-α and acetyl-coenzyme A carboxylase phosphorylation, diminished fatty acid oxidation, increased serine palmitoyltransferase expression, and enhanced ceramide formation compared with normal islets. Importantly, human islets overexpressing HGF also display increased β-cell apoptosis in the presence of palmitate. Treatment of both mouse andhumanislet cells with the de novo ceramide synthesis inhibitors myriocin and fumonisin B1 abrogates β-cell apoptosis induced by HGF and palmitate. Collectively, these studies indicate that HGF can be detrimental for β-cell survival in an environment with excessive fatty acid supply.